title: NF-κB pathway is involved in CRP-induced effects on pulmonary arterial endothelial cells in chronic thromboembolic pulmonary hypertension.
abstract: Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by thrombofibrotic obstruction of proximal pulmonary arteries. The cellular and molecular mechanisms underlying the pathogenesis remain incompletely understood, although we recently evidenced the potential involvement of the inflammatory marker C-reactive protein (CRP). We aimed to investigate the intracellular mechanisms induced by CRP in proximal pulmonary arterial endothelial cells (PAEC). PAEC were isolated from vascular material obtained during pulmonary endarterectomy. RNA was extracted from CRP-stimulated PAEC, and first-stand cDNA was generated. A RT(2) profiler PCR Array was used to evaluate the expression of 84 key genes related to NF-κB-mediated signal transduction. CRP-induced NF-κB activation was studied. The effects of pyrrolidine-dithio-carbamate ammonium (PDTC), an inhibitor of the NF-κB pathway, were investigated on CRP-induced adhesion of monocytes to PAEC, adhesion molecule expression, endothelin-1 (ET-1), interleukin-6 (IL-6), and von Willebrand factor (vWF) secretion. Compared with nonstimulated PAEC, serotonin receptor 2B was downregulated by 25%, inhibitor of NF-κB kinase subunit epsilon (IKBKE) by 30%, and toll-like receptor-4 and -6 by 18 and 39%, respectively, in CRP-stimulated PAEC. The transcription factor FOS was threefold upregulated. CRP induced RelA/NF-κBp65 phosphorylation. PDTC dose dependently inhibited the adhesion of monocytes to CRP-stimulated PAEC. PDTC also inhibited the CRP-induced expression of ICAM-1 at the surface of PAEC. PDTC impaired the secretion of ET-1 by 18% and tended to inhibit the secretion of IL-6 by CRP-stimulated PAEC by 46%. PDTC did not inhibit the CRP-induced secretion of vWF. These results suggest an involvement of the NF-κB pathway in mediating different effects of CRP on proximal CTEPH-PAEC.
authors.affiliation: Respiratory Division, Dept. of Clinical and Experimental Medicine - KU Leuven, Onderwijs & Navorsing 1-Box 706, Herestraat 49, B-3000 Leuven, Belgium. rozenn.quarck@med.kuleuven.be.
authors.forename: Marijke
authors.initials: M
authors.lastname: Wynants
authors.forename: Leanda
authors.initials: L
authors.lastname: Vengethasamy
authors.forename: Alicja
authors.initials: A
authors.lastname: Ronisz
authors.forename: Bart
authors.initials: B
authors.lastname: Meyns
authors.forename: Marion
authors.initials: M
authors.lastname: Delcroix
authors.forename: Rozenn
authors.initials: R
authors.lastname: Quarck
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002097:C-Reactive Protein / Q000378:metabolism*; D002478:Cells, Cultured; D002908:Chronic Disease; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D011651:Pulmonary Artery / Q000166:cytology / Q000378:metabolism*; D011655:Pulmonary Embolism / Q000150:complications / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D016328:NF-kappa B; D018799:Intercellular Adhesion Molecule-1; D002097:C-Reactive Protein
keywords: C-reactive protein; NF-κB; chronic thromboembolic pulmonary hypertension; endothelial cells